The histopathologic type of the periampullary tumors. Is it important for survival
St.O. Georgescu, C.N. Neacsu, D. Vintilã, P. Popa, N. Florea, M.S. MihailoviciOriginal article, no. 6, 2009
* 1st Surgical Clinic, Sf. Spiridon Hospital, Gr.T. Popa UMPh Iasi, Romania
* 1st Surgical Clinic, Sf. Spiridon Hospital, Gr.T. Popa UMPh Iasi, Romania
* Department of Pathology, Sf. Spiridon Hospital, Iasi, Romania
* Department of Pathology, Gr.T. Popa University of Medicine and Pharmacy Iasi, Romania
* 1st Surgical Clinic, Sf. Spiridon Hospital, Gr.T. Popa UMPh Iasi, Romania
* Department of Pathology, Sf. Spiridon Hospital, Iasi, Romania
* Department of Pathology, Gr.T. Popa University of Medicine and Pharmacy Iasi, Romania
Introduction
In 1710, Abraham Vater (1684-1751), professor at Wittenberg, described the structure hight with his name but the results of his research were published in 1720. The Ampulla of Vater is an anatomical complex which represents the junction between the duoden and the end of the ductal pancreatic and biliary systems. Although this area of duodenum has a diameter of only one centimeter, it is characterized by the highest incidence of the intestinal neoplasies (1). The tumors of this region are named periampullary adenocarcinomas. In 1994, Kimura and coworkers described two main histological types of periampullary tumors, the intestinal and pancreatobiliary types (2). This classification is now widely accepted for ampullary carcinoma with some few reappraisals performed by others (3). Recently some studies disclosed the worse prognostic significance of the pancreatobiliary type of these malignancies (4,5).
Material and Methods
We reviewed the medical records of 46 patients who underwent pancreatoduodenectomy in our service for vaterian carcinoma during ten years period (1998-2007). We included in our study only 38 patients with R0-R1 resections, 23 men (60.5%) and 15 women (39.5%) with median age 61 years (range 31-73).
The surgery consisted in Whipple (n=22; 57.9%) and Traverso-Longmire (n=16; 42.1%) procedures. We took out from the patients register cards the data considering to tumors stage and size, regional lymph nodes involved, differentiation degree, and the survival time after surgery (table 1).
The histopathologic samples were reviewed by two senior pathologists concerning to histologic type of the tumors (intestinal vs. pancreatobiliary type) according to the criteria suggested by Kimura (2) and Albores-Saavedra (3). The mixed type was observed in 21 cases (55.2%), but we categorized these tumors according to the dominant pattern recommended by Westgaard (4) (table 1).
Statistics
We used non-parametric descriptors (median, range), chi-square test for simple comparisons, and Spearman’s Rank Correlation test. The Kaplan-Meier method was used to estimate median survival and to obtain the curves for overall survival. The survival curves were compared using log-rank test. A multivariable Cox regression analysis of histopathologic prognostic factors was performed using forward-stepwise method. A p value of 0.05 (two sided) was taken as the limit of significance.
Results
Even we found more periampullary carcinomas with dominant intestinal type (n=23; 63.5%), the difference between this pattern and the pancreatobiliary type is insignificant (chi square).
The pancreatobiliary type of the tumor is significant correlate (Spearman’s rank) only with the lower degree of differentiation; our data suggest the greater importance of this last variable significant correlated with all histolopatologic factors included in analysis (table 2).
At the endpoint of the study we registered eight survivors. In these cases the median time from pancreato-duodenectomy is 17 months (range 9 to 96 months). The Kaplan-Meier method showed high significant differences in median overall survival favorable to the lower tumor stage, the absence of lymph nodes metastasis and to the well differentiates carcinomas (table 3). The intestinal type has a good survival comparing with pancreatobiliary type (fig. 1).
In a multivariable Cox regression analysis we included the following variables: age, gender, surgery type (Whipple vs. Traverso-Longmire), tumor stage, tumor size, regional lymph nodes involvement, differentiation degree and histological type. Using forward-stepwise method, we found only two categorical variables associated with a high risk to death: the presence of regional lymph nodes metastasis and the differentiation degree of the tumor (table 4).
According to these results the pancreatobiliary type of the periampullary tumors has a poor overall survival but the histologic type of the tumor isn’t an independent prognostic factor.
Discussions
It is more difficult to assess the real origin of the periampullary carcinoma. For example a ductal carcinoma of the pancreatic head with a diameter exceeding 3 cm can invade the entire region of the ampulla of Vater (7). Furthermore the ductal pancreatic carcinoma may develop intestinal patterns (8). To determine the real origin of the tumor it is necessary a global evaluation of the resected specimen with an accurate examination of the ductal structures. A retrospective study has at command only the microscopic samples, but in a prospective research it is possible the implementation of a standard protocol like in Westgaard’s study recently published (4).
The immunohistochemistry has a title part to solve the ambiguous origin of some periampullary tumors (9). The intestinal type of these malignancies express the markers Mucin 2 (MUC 2) and CDX2 similarly to other intestinal tumors, mucinous tumors and those with seal ring cells (10). On the contrary, pancreatobiliary carcinomas express Mucin 1 (MUC1) and Cytokeratin 17 (CK17) (10). Likewise, gastric mucin (MUC5AC) and gastric transcription factor SOX2 are associated with the pancreatobiliary phenotype of the vaterian carcinoma (11).
Ample studies which have included the systematic immunohistochemical testing of the adenocarcinomas of the Ampulla of Vater pointed out that the intestinal type is the most frequent (12-15). The intestinal type of the ampullary carcinoma has a higher rate of resectability and a significantly better prognosis following pancreatoduodenectomy (16).
The vessel involvement and the perineural infiltration could not be assessed in our retrospective study, but these features are also important for prognostic after pancreatoduodenectomy (4).
We had a small study group, but our results rather confirm the importance of the histologic type of the periampullary adenocarcinomas. A prospective multicenter approach with minimal bias risk could be performed to dignify the importance of this histologic factor.
Conclusion
The intestinal type of periampullary adenocarcinomas has a significant long survival, but the lymph nodes involvement and the lower degree of differentiation are associated with a high risk of death in vaterian malignancies.
References
1. SOHN, T.A., LILLEMOE, K.D. - Tumors of the gallblader, bile ducts and ampulla. în “Gastrointestinal and Liver Disease”, sub redactia Sleisenger & Fordtran's, Ed. Saunders, 2002, pag. 1153 - 1166.
2. KIMURA, W., FUTAKAWA, N., YAMAGATA, S., WADA, Y., KURODA, A., MUTO, T., ESAKI, Y. - Different clinicopathologic findings in two histologic types of carcinoma of papilla of Vater. Jpn. J. Cancer Res., 1994, 85:161.
3. ALBORES-SAAVEDRA, J., HENSON, D.E., KLIMSTRA, D.S. - Atlas of tumor pathology: tumors of the gallblader, extrahepatic bile ducts, and ampulla of Vater, 3rd series, fascicle 27. Armed Forces Institute of Pathology (Washington, D.C.), 2000.
4. WESTGAARD, A., TAFJORD, S., FARSTAD, I.N., CVANCAROVA, M., EIDE, T.J., MATHISEN, O., CLAUSEN, O.P.F., GLADHAUG, I.P. - Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. B.M.C. Cancer DOI: 10.1186/1471-2407-8-170.
5. SCHIRMACHER, P., BÜCHLER, M.W. - Ampullary adenocarcinoma – differentiation matters. B.M.C. Cancer DOI: 10.1186/1471-2407-8-251.
6. ZHOU, H., SCHAEFER, N., WOLFF, M., FISCHER, H.P. - Carcinoma of the ampulla of Vater: comparative histologic/ immunohistochemical classification and follow-up. Am. J. Surg. Pathol., 2004, 28:875.
7. FISHER, W., BAKEY, M. - Differences between ampullary, periampullary and pancreatic cancer. World J. Surg., 2007, 31:144.
8. ALBORES-SAAVEDRA, J., SIMPSON, K., DANCER, Y.J., HRUBAN, R. - Intestinal type adenocarcinoma: a previously unrecognized histologic variant of ductal carcinoma of the pancreas. Ann. Diagn. Pathol., 2007, 11:3.
9. POPESCU, I., STROESCU, C., DUMITRAŞCU, T., HERLEA, V., PÂSLARU, L., LAZÃR, V., BOISSIN, H., TAIEB, J., HOREANGA, I. - Digestive tumor bank protocol: from surgical specimen to the genomic studies of digestive cancer. Chirurgia (Bucur.), 2006, 101:471.
10. CHU, P.G., SCHWARZ, R.E., LAU, S.K., YEN, Y., WEISS, L.M. - Immunohistochemical staining in the diagnosis of pancreatobiliary and ampula of Vater’s adenocarcinoma: application of CDX2, CK17, MUC1 and MUC2. Am. J. Surg. Pathol., 2005, 29:359.
11. SANADA, Y., YOSHIDA, K., KONISHI, K., OEDA, M., OHARA, M., TSUTANI, Y. - Expression of gastric mucin MUC5AC and gastric transcription factor SOX2 in ampulla of vater adenocarcinoma: comparison between expression patterns and histologic subtypes. Oncol. Rep., 2006, 15:1157.
12. HOWE, J.R., KLIMSTRA, D.S., MOCCIA, R.D., CONLON, K.C., BRENNAN, M.F. - Factors predictive of survival in ampullary carcinoma. Ann. Surg., 1998, 228:87.
13. KEVIN, C.P. - Carcinoma of the ampulla of Vater: a distinct disease entity? Ann. Surg. Oncol., 2003, 10:1136.
14. MC CARTHY, D.M., HRUBAN, R.H., ARGANI, P. - Role of DPC4 tumor suppressor gene in adenocarcinoma of the ampulla of Vater: an analysis of 140 cases. Mod. Pathol., 2003, 16:272.
15. TODOROKI, T., KOIKE, N., MORISHITA, Y. - Patterns and predictors of failure after curative resection of carcinoma of the ampulla vater. Ann. Surg. Oncol., 2003, 10:1176.
16. TALAMINI, M.A., MOESINGER, R.C., PITT, H.A. - Adenocarcinoma of the ampulla of Vater-a 28 year experience. Ann. Surg., 1997, 225:590.
In 1710, Abraham Vater (1684-1751), professor at Wittenberg, described the structure hight with his name but the results of his research were published in 1720. The Ampulla of Vater is an anatomical complex which represents the junction between the duoden and the end of the ductal pancreatic and biliary systems. Although this area of duodenum has a diameter of only one centimeter, it is characterized by the highest incidence of the intestinal neoplasies (1). The tumors of this region are named periampullary adenocarcinomas. In 1994, Kimura and coworkers described two main histological types of periampullary tumors, the intestinal and pancreatobiliary types (2). This classification is now widely accepted for ampullary carcinoma with some few reappraisals performed by others (3). Recently some studies disclosed the worse prognostic significance of the pancreatobiliary type of these malignancies (4,5).
Material and Methods
We reviewed the medical records of 46 patients who underwent pancreatoduodenectomy in our service for vaterian carcinoma during ten years period (1998-2007). We included in our study only 38 patients with R0-R1 resections, 23 men (60.5%) and 15 women (39.5%) with median age 61 years (range 31-73).
The surgery consisted in Whipple (n=22; 57.9%) and Traverso-Longmire (n=16; 42.1%) procedures. We took out from the patients register cards the data considering to tumors stage and size, regional lymph nodes involved, differentiation degree, and the survival time after surgery (table 1).
The histopathologic samples were reviewed by two senior pathologists concerning to histologic type of the tumors (intestinal vs. pancreatobiliary type) according to the criteria suggested by Kimura (2) and Albores-Saavedra (3). The mixed type was observed in 21 cases (55.2%), but we categorized these tumors according to the dominant pattern recommended by Westgaard (4) (table 1).
Statistics
We used non-parametric descriptors (median, range), chi-square test for simple comparisons, and Spearman’s Rank Correlation test. The Kaplan-Meier method was used to estimate median survival and to obtain the curves for overall survival. The survival curves were compared using log-rank test. A multivariable Cox regression analysis of histopathologic prognostic factors was performed using forward-stepwise method. A p value of 0.05 (two sided) was taken as the limit of significance.
Results
Even we found more periampullary carcinomas with dominant intestinal type (n=23; 63.5%), the difference between this pattern and the pancreatobiliary type is insignificant (chi square).
The pancreatobiliary type of the tumor is significant correlate (Spearman’s rank) only with the lower degree of differentiation; our data suggest the greater importance of this last variable significant correlated with all histolopatologic factors included in analysis (table 2).
At the endpoint of the study we registered eight survivors. In these cases the median time from pancreato-duodenectomy is 17 months (range 9 to 96 months). The Kaplan-Meier method showed high significant differences in median overall survival favorable to the lower tumor stage, the absence of lymph nodes metastasis and to the well differentiates carcinomas (table 3). The intestinal type has a good survival comparing with pancreatobiliary type (fig. 1).
In a multivariable Cox regression analysis we included the following variables: age, gender, surgery type (Whipple vs. Traverso-Longmire), tumor stage, tumor size, regional lymph nodes involvement, differentiation degree and histological type. Using forward-stepwise method, we found only two categorical variables associated with a high risk to death: the presence of regional lymph nodes metastasis and the differentiation degree of the tumor (table 4).
According to these results the pancreatobiliary type of the periampullary tumors has a poor overall survival but the histologic type of the tumor isn’t an independent prognostic factor.
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It is more difficult to assess the real origin of the periampullary carcinoma. For example a ductal carcinoma of the pancreatic head with a diameter exceeding 3 cm can invade the entire region of the ampulla of Vater (7). Furthermore the ductal pancreatic carcinoma may develop intestinal patterns (8). To determine the real origin of the tumor it is necessary a global evaluation of the resected specimen with an accurate examination of the ductal structures. A retrospective study has at command only the microscopic samples, but in a prospective research it is possible the implementation of a standard protocol like in Westgaard’s study recently published (4).
The immunohistochemistry has a title part to solve the ambiguous origin of some periampullary tumors (9). The intestinal type of these malignancies express the markers Mucin 2 (MUC 2) and CDX2 similarly to other intestinal tumors, mucinous tumors and those with seal ring cells (10). On the contrary, pancreatobiliary carcinomas express Mucin 1 (MUC1) and Cytokeratin 17 (CK17) (10). Likewise, gastric mucin (MUC5AC) and gastric transcription factor SOX2 are associated with the pancreatobiliary phenotype of the vaterian carcinoma (11).
Ample studies which have included the systematic immunohistochemical testing of the adenocarcinomas of the Ampulla of Vater pointed out that the intestinal type is the most frequent (12-15). The intestinal type of the ampullary carcinoma has a higher rate of resectability and a significantly better prognosis following pancreatoduodenectomy (16).
The vessel involvement and the perineural infiltration could not be assessed in our retrospective study, but these features are also important for prognostic after pancreatoduodenectomy (4).
We had a small study group, but our results rather confirm the importance of the histologic type of the periampullary adenocarcinomas. A prospective multicenter approach with minimal bias risk could be performed to dignify the importance of this histologic factor.
Conclusion
The intestinal type of periampullary adenocarcinomas has a significant long survival, but the lymph nodes involvement and the lower degree of differentiation are associated with a high risk of death in vaterian malignancies.
References
1. SOHN, T.A., LILLEMOE, K.D. - Tumors of the gallblader, bile ducts and ampulla. în “Gastrointestinal and Liver Disease”, sub redactia Sleisenger & Fordtran's, Ed. Saunders, 2002, pag. 1153 - 1166.
2. KIMURA, W., FUTAKAWA, N., YAMAGATA, S., WADA, Y., KURODA, A., MUTO, T., ESAKI, Y. - Different clinicopathologic findings in two histologic types of carcinoma of papilla of Vater. Jpn. J. Cancer Res., 1994, 85:161.
3. ALBORES-SAAVEDRA, J., HENSON, D.E., KLIMSTRA, D.S. - Atlas of tumor pathology: tumors of the gallblader, extrahepatic bile ducts, and ampulla of Vater, 3rd series, fascicle 27. Armed Forces Institute of Pathology (Washington, D.C.), 2000.
4. WESTGAARD, A., TAFJORD, S., FARSTAD, I.N., CVANCAROVA, M., EIDE, T.J., MATHISEN, O., CLAUSEN, O.P.F., GLADHAUG, I.P. - Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. B.M.C. Cancer DOI: 10.1186/1471-2407-8-170.
5. SCHIRMACHER, P., BÜCHLER, M.W. - Ampullary adenocarcinoma – differentiation matters. B.M.C. Cancer DOI: 10.1186/1471-2407-8-251.
6. ZHOU, H., SCHAEFER, N., WOLFF, M., FISCHER, H.P. - Carcinoma of the ampulla of Vater: comparative histologic/ immunohistochemical classification and follow-up. Am. J. Surg. Pathol., 2004, 28:875.
7. FISHER, W., BAKEY, M. - Differences between ampullary, periampullary and pancreatic cancer. World J. Surg., 2007, 31:144.
8. ALBORES-SAAVEDRA, J., SIMPSON, K., DANCER, Y.J., HRUBAN, R. - Intestinal type adenocarcinoma: a previously unrecognized histologic variant of ductal carcinoma of the pancreas. Ann. Diagn. Pathol., 2007, 11:3.
9. POPESCU, I., STROESCU, C., DUMITRAŞCU, T., HERLEA, V., PÂSLARU, L., LAZÃR, V., BOISSIN, H., TAIEB, J., HOREANGA, I. - Digestive tumor bank protocol: from surgical specimen to the genomic studies of digestive cancer. Chirurgia (Bucur.), 2006, 101:471.
10. CHU, P.G., SCHWARZ, R.E., LAU, S.K., YEN, Y., WEISS, L.M. - Immunohistochemical staining in the diagnosis of pancreatobiliary and ampula of Vater’s adenocarcinoma: application of CDX2, CK17, MUC1 and MUC2. Am. J. Surg. Pathol., 2005, 29:359.
11. SANADA, Y., YOSHIDA, K., KONISHI, K., OEDA, M., OHARA, M., TSUTANI, Y. - Expression of gastric mucin MUC5AC and gastric transcription factor SOX2 in ampulla of vater adenocarcinoma: comparison between expression patterns and histologic subtypes. Oncol. Rep., 2006, 15:1157.
12. HOWE, J.R., KLIMSTRA, D.S., MOCCIA, R.D., CONLON, K.C., BRENNAN, M.F. - Factors predictive of survival in ampullary carcinoma. Ann. Surg., 1998, 228:87.
13. KEVIN, C.P. - Carcinoma of the ampulla of Vater: a distinct disease entity? Ann. Surg. Oncol., 2003, 10:1136.
14. MC CARTHY, D.M., HRUBAN, R.H., ARGANI, P. - Role of DPC4 tumor suppressor gene in adenocarcinoma of the ampulla of Vater: an analysis of 140 cases. Mod. Pathol., 2003, 16:272.
15. TODOROKI, T., KOIKE, N., MORISHITA, Y. - Patterns and predictors of failure after curative resection of carcinoma of the ampulla vater. Ann. Surg. Oncol., 2003, 10:1176.
16. TALAMINI, M.A., MOESINGER, R.C., PITT, H.A. - Adenocarcinoma of the ampulla of Vater-a 28 year experience. Ann. Surg., 1997, 225:590.